Hepatitis B virus (HBV) is a major cause of serious liver diseases, including chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) throughout the world and the US, especially among minorities such as African Americans, Native Americans, and Asian Americans. Yet, the molecular mechanisms of carcinogenesis in chronic hepatitis B remain controversial. Although it is clear that non-specific factors such as chronic inflammation and dietary carcinogens play important roles, there are no firm data on how HBVspecific factors may contribute to carcinogenesis. Recent clinical data have pointed to an association between HCC and HBV mutants with in-frame deletions and/or missense start codon mutation in the preS2 region of the surface gene. More importantly, we have generated transgenic mice containing a preS2 mutant HBV genome and shown that they develop HCC. We hypothesize that such preS2 HBV mutants induce stress in the endoplasmic reticulum, by virtue of an abnormal amount and/or form of the HBV surface proteins. Prolonged activation of the stress pathway and perhaps other signaling pathways in turn leads to HCC formation, with cooperation from other HBV factors as well as non-specific factors. We will test this hypothesis by using the transgenic mice we have generated that contain a preS2 mutant HBV genome. We will investigate if liver inflammation or a HCC-associated core promoter mutation can cooperate with the preS2 mutant HBV to cause HCC. We will then use both focused studies and gene array approaches to begin understanding the cellular pathways regulated by the preS2 mutant HBV. Finally, we will generate new transgenic mouse lines to determine the exact carcinogenic trans-acting factor(s) synthesized by this mutant. It is anticipated that these experiments will provide a detailed understanding of the molecular basis for carcinogenesis in HBV-infected people and thus point to ways for designing novel preventive and therapeutic measures for this deadly disease. Hepatitis B virus is a major cause of suffering and death in the world, by causing liver injury, cirrhosis (liver scarring) and liver cancer. It is the second most deadly human virus, after human immunodeficiency virus, and causes more than 1.2 million deaths annually. Current treatment is expensive and inadequate, and we hope that our research can lead to the development of new ways to prevent, detect, or treat liver cancer in these patients..